Olvanil, a non-pungent vanilloid enhances the gastrointestinal toxicity of cisplatin in the ferret.

Abstract

Pungent transient receptor potential vanilloid (TRPV1) channel activators have been shown to have broad inhibitory anti-emetic activity against centrally- and peripherally acting challenges but only at doses that have adverse effects on the cardiovascular system and on temperature homeostasis. In the present studies, we investigated the anti-emetic potential of the non-pungent TRPV1 activator, olvanil (0.05-5 mg/kg, s.c., 3 times per day, for 3 days) to antagonise the acute and delayed emesis induced by cisplatin (5 mg/kg, i.p.) in ferrets that had been implanted with radiotelemetry devices to enable an analysis of heart rate and temperature. Cisplatin induced an acute (day 1: 48.0+/-18.3 retches+vomits) and delayed (day 2: 111.7+/-35.5; day 3: 147.5+/-20.2 retches+vomits) emetic response that was associated with reduced food (-98.7% at day 3, P<0.001) and water consumption (-70.2% at day 3, P<0.001) and progressive weight loss (-12.0% at day 3, P<0.001). Olvanil did not prevent either emesis or the weight loss and negative effects on food and water consumption (P>0.05); the effect on food consumption appeared potentiated by a further 21.2% at 0.05 mg/kg (P<0.05) and 19.9% at 0.5 mg/kg (P<0.05). Cisplatin did not alter body temperature (basal: 37.7+/-0.1 degrees C) or heart rate (basal: 233.7+/-5.5 beats per min (BPM); P>0.05), but hypothermia (-1.6 degrees C) and increases in locomotor activity (50-90%) were recorded in animals concomitantly treated with olvanil (P<0.05). These data indicate that non-pungent activators as exemplified by olvanil are unlikely to be useful clinically for the control of the gastrointestinal side effects induced by cisplatin.

• Authors: Kit-Man Chu, Man-Piu Ngan, Man-Keung Wai, Chi-Kong Yeung, Paul L R Andrews, Nathalie Percie du Sert, Ge Lin, John A Rudd
• Journal: Toxicology letters (Toxicol Lett) Vol. 192 Issue 3 Pg. 402-7 (Feb 15 2010) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 19931602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• TRPV Cation Channels
• olvanil
• Cisplatin
• Capsaicin

Topics

• Animals
• Antineoplastic Agents (adverse effects)
• Body Temperature (drug effects)
• Capsaicin (analogs & derivatives, pharmacology)
• Cisplatin (adverse effects)
• Drinking (drug effects)
• Eating (drug effects)
• Ferrets
• Heart Rate (drug effects)
• Male
• Motor Activity (drug effects)
• TRPV Cation Channels (agonists)
• Vomiting (chemically induced, drug therapy)